Thyroid hormones, such as L-thyroxine (T4) and 3, 5, 3′-triiodo-L-thyronine (T3), and their analogues such as GC-1, DITPA, tetraiodothyroacetic acid (tetrac) and triiodothyroacetic acid (triac), regulate many different physiological processes in different tissues in vertebrates. It was previously known that many of the actions of thyroid hormones are mediated by the thyroid hormone receptor (“TR”) and a novel cell surface receptor for thyroid hormone (L-thyroxine, T4; T3) integrin αvβ3, at or near the Arg-Gly-Asp (RGD) recognition site on the integrin. The integrin receptor is not a homologue of the nuclear thyroid hormone receptor (TR), but activation of this cell surface receptor results in a number of nucleus-mediated events. A detailed description of the thyroid hormones, analogs thereof and their properties have been fully discussed and disclosed in US Patent Publication No. 2011/0052715A1 to Davis et al., U.S. Pat. No. 7,785,632 to Mousa et al., and U.S. Pat. No. 8,668,926 to Mousa et al., incorporated by reference in their entirety herein.
Evidence that thyroid hormone can act primarily outside the cell nucleus has come from studies of mitochondrial responses to T3 and diiodothyronine (T2), from rapid onset effects of the hormone at the cell membrane, and from actions on cytoplasmic proteins. The recent description of a plasma membrane receptor for thyroid hormone on integrin αvβ3 has provided some insight into effects of the hormone on membrane ion pumps, such as the Na+/H+ anti porter, and has led to the description of interfaces between actions initiated at the membrane thyroid hormone receptor and nuclear events that underlie important cellular or tissue processes, such as, for example, angiogenesis and proliferation of certain tumor cells.
Inflammation is closely linked to cancer. Chronic inflammation increases the risk for various cancers, indicating that eliminating inflammation may represent a valid strategy for cancer prevention and therapy. There is data suggesting that inflammation plays a role in the establishment, progression, and/or aggressiveness of various malignancies. As a tumor develops, it expresses phenotypes similar to inflammatory cells. Molecular mediators and their respective receptors have a significant impact on angiogenesis, cell migration, and metastasis. Given its myriad pro-tumor effects, inflammation has become a target for cancer prevention and therapy. COX-2 (cyclooxygenase 2, PTGS2) is the most frequently evaluated anti-cancer anti-inflammatory target, although numerous other targets, such as NF-kB, cytokines/cytokine receptors, chemokines/chemokine receptors, FGF/FGFR (fibroblast growth factor/receptor), and VEGF have also been examined. While initial studies focused on various broad-spectrum NSAIDs (which non-specifically inhibit both COX-1 and COX-2), more recent studies have examined COX-2 specific agents, such as celecoxib. However, given the GI toxicity and non-specific activity of NSAIDs, and the cardio-toxicity of specific COX-2 inhibitors, the use of such agents remains controversial. Therefore, a need exists for the combined use of an effective anti-cancer agent, anti-angiogenic agent and an anti-inflammatory agent capable of being selectively targeted to the tumor cells and reduces inflammation while reducing the toxicity caused by unselective anti-inflammatory agents.